Understanding the therapeutic action of antipsychotics: from molecular to cellular targets with focus on the islands of Calleja

IF 4.5 2区医学 Q1 CLINICAL NEUROLOGY

International Journal of Neuropsychopharmacology Pub Date : 2024-04-17 DOI:10.1093/ijnp/pyae018

Merve Direktor, Peter Gass, Dragos Inta

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Abstract

The understanding of the pathophysiology of schizophrenia as well as the mechanisms of action of antipsychotic drugs remains a challenge for psychiatry. The demonstration of the therapeutic efficacy of several new atypical drugs targeting multiple different receptors apart from the classical dopamine D2 receptor as initially postulated unique antipsychotic target, complicated even more conceptualization efforts. Here we discuss results suggesting a main role of the islands of Calleja, still poorly studied GABAergic granule cell clusters in the ventral striatum, as cellular targets of several innovative atypical antipsychotics (clozapine, cariprazine and xanomeline/emraclidine) effective in treating also negative symptoms of schizophrenia. We will emphasize the potential role of dopamine D3 and M4 muscarinic acetylcholine receptor expressed at highest level by the islands of Calleja, as well as their involvement in schizophrenia-associated neurocircuitries. Finally, we will discuss the implications of new data showing ongoing adult neurogenesis of the islands of Calleja, as a very promising antipsychotic target linking long-life neurodevelopment and dopaminergic dysfunction in the striatum.

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了解抗精神病药物的治疗作用：从分子靶点到细胞靶点，重点关注卡列哈岛

了解精神分裂症的病理生理学以及抗精神病药物的作用机制仍然是精神病学面临的一项挑战。除了最初推测的独特抗精神病靶点--经典的多巴胺 D2 受体外，几种新型非典型药物针对多种不同受体的疗效得到了证实，这使得概念化工作变得更加复杂。在这里，我们将讨论一些结果，这些结果表明，腹侧纹状体中的卡列哈岛（GABA能颗粒细胞簇）作为几种创新的非典型抗精神病药物（氯氮平、卡瑞普嗪和沙诺美林/恩拉西定）的细胞靶点，在治疗精神分裂症的阴性症状方面发挥着主要作用。我们将强调多巴胺 D3 和 M4 毒蕈碱乙酰胆碱受体在卡列哈岛表达水平最高的潜在作用，以及它们在精神分裂症相关神经回路中的参与。最后，我们将讨论新数据的意义，这些数据显示卡列哈岛的成年神经发生正在进行中，这是一个非常有前景的抗精神病靶点，它将长寿命神经发育和纹状体多巴胺能功能障碍联系在一起。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Neuropsychopharmacology 医学-精神病学

CiteScore

8.40

自引率

2.10%

发文量

230

审稿时长

4-8 weeks

期刊介绍： The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.

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